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Aldosterone Insufficiency Contributes to Calcineurin Inhibitor‐induced Hyperkalemia
Author(s) -
Berber Mesut,
Leng Sining,
Breault David,
Beuschlein Felix,
Loffing Johannes,
Penton David
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03091
Subject(s) - endocrinology , aldosterone , medicine , calcineurin , reabsorption , mineralocorticoid , renal sodium reabsorption , homeostasis , zona glomerulosa , chemistry , adrenal cortex , biology , kidney , receptor , transplantation , angiotensin ii
The mineralocorticoid aldosterone promotes renal K + excretion and Na + reabsorption; thereby it is critical for the regulation of ion homeostasis and blood pressure. Interestingly, immunosuppression therapy with protein phosphatase 3 (calcineurin) inhibitors often results in rather low plasma aldosterone levels despite a concomitant hyperkalemia and hyperreninemia. Calcineurin (Cn) is a calcium and calmodulin‐dependent protein phosphatase expressed in the adrenal cortex. We tested the hypothesis that Cn participates in the signal transduction pathway mediating the K + ‐dependent stimulation of aldosterone production. To address this question, we used the adrenocortical cell model NCI‐H295R, mouse and human ex vivo adrenal preparations and a ZG‐specific and inducible Cn‐beta subunit 1 (CnB1) knockout mouse model (ZG‐CnB1‐KO). Inhibition of Cn with tacrolimus abolished the K + ‐stimulated expression of CYP11B2 in NCI‐H295R cell line as well as in mouse and human adrenal pieces, ex vivo . Moreover, high K + diet‐dependent increase in aldosterone production was blunted in wild type mice treated with tacrolimus. Furthermore, male ZG‐CnB1‐KO mice fed a high K + diet exhibited a decreased aldosterone excretion compared to control animals while ZG‐CnB1‐KO females became hyperkalemic. Using a phosphoproteomics analysis, we identified the nuclear factor of activated T‐cells, cytoplasmic 4 (NFATc4) as a downstream factor regulated by Cn. The genetic deletion of NFATc4 in NCI‐H295R cells reduced the basal expression of CYP11B2 and blunted the K + ‐stimulated expression of this gene. Conversely, the expression of a constitutively active form of NFATc4 in NCI‐H295R cells drastically increased the expression of CYP11B2 which remained unaltered upon treatment with K + or tacrolimus. Altogether, our data indicate that the calcineurin‐NFATc4 pathway is activated by K + to promote adrenal aldosterone production. Moreover, our data indicate that insufficient aldosterone production contributes to Cn inhibitor‐induced hyperkalemia.